Peringatan Keamanan

Oral LD50 of sirolimus is 800 mg/kg in rats and 2500 mg/kg in mouse.L39302

Sirolimus is a narrow therapeutic index drug.A242412 Although there are reports of overdose with sirolimus, there is limited information on overdose in the clinical setting. Symptoms of overdose are consistent with the adverse effects of sirolimus. General supportive measures are recommended in the event of an overdose. Because sirolimus has low aqueous solubility and high erythrocyte and plasma protein binding, it is not expected to be dialyzable to any significant extent.L19809

Sirolimus

DB00877

small molecule approved investigational

Deskripsi

Sirolimus, also known as rapamycin, is a macrocyclic lactone antibiotic produced by bacteria Streptomyces hygroscopicus, which was isolated from the soil of the Vai Atari region of Rapa Nui (Easter Island).A242412 It was first isolated and identified as an antifungal agent with potent anticandida activity; however, after its potent antitumor and immunosuppressive activities were later discovered, it was extensively investigated as an immunosuppressive and antitumour agent.A13448 Its primary mechanism of action is the inhibition of the mammalian target of rapamycin (mTOR), which is a serine/threonine-specific protein kinase that regulates cell growth, proliferation, and survival. mTOR is an important therapeutic target for various diseases, as it was shown to regulate longevity and maintain normal glucose homeostasis.A242417 Targeting mTOR received more attention especially in cancer, as mTOR signalling pathways are constitutively activated in many types of human cancer.A1320

Sirolimus was first approved by the FDA in 1999 for the prophylaxis of organ rejection in patients aged 13 years and older receiving renal transplants.A242372 In November 2000, the drug was recognized by the European Agency as an alternative to calcineurin antagonists for maintenance therapy with corticosteroids.A242412 In May 2015, the FDA approved sirolimus for the treatment of patients with lymphangioleiomyomatosis.L39292 In November 2021, albumin-bound sirolimus for intravenous injection was approved by the FDA for the treatment of adults with locally advanced unresectable or metastatic malignant perivascular epithelioid cell tumour (PEComa).L39267 Sirolimus was also investigated in other cancers such as skin cancer, Kaposi’s Sarcoma, cutaneous T-cell lymphomas, and tuberous sclerosis.A242372 The topical formulation of sirolimus, marketed as HYFTOR, was approved by the FDA in April 2022: this marks the first topical treatment approved in the US for facial angiofibroma associated with tuberous sclerosis complex.L41494

Struktur Molekul 2D

Berat 914.187
Wujud solid

Peta Jejaring Molekuler
Legenda: Obat • Target • Gen • Enzim • (Panah → menunjukkan arah efek / relasi) • Transporter • Carrier

Profil Farmakokinetik

Waktu Paruh (Half-Life) The mean ± SD terminal elimination half-life (t½) of sirolimus after multiple dosing in stable renal transplant patients was estimated to be about 62 ± 16 hours.[L19809]
Volume Distribusi The mean (± SD) blood-to-plasma ratio of sirolimus was 36 ± 18 L in stable renal allograft patients, indicating that sirolimus is extensively partitioned into formed blood elements. The mean volume of distribution (V<sub>ss/F</sub>) of sirolimus is 12 ± 8 L/kg.[L19809]
Klirens (Clearance) In adult renal transplant patients with low- to moderate-immunologic risk, oral administration of 2 mg sirolimus led to oral clearance of 173 ± 50 mL/h/kg for oral solution and 139 ± 63 mL/h/kg for oral tablets.[L19809]

Absorpsi

In adult renal transplant patients with low- to moderate-immunologic risk, oral administration of 2 mg sirolimus led to a Cmax of 14.4 ± 5.3 ng/mL for oral solution and 15.0 ± 4.9 ng/mL for oral tablets. The tmax was 2.1 ± 0.8 hours for oral solution and 3.5 ± 2.4 hours for oral tablets. In healthy subjects, the tmax is one hour. In a multi-dose study, steady-state was reached six days following repeated twice-daily administration without an initial loading dose, with the average trough concentration of sirolimus increased approximately 2- to 3-fold. It is suspected that a loading dose of three times the maintenance dose will provide near steady-state concentrations within one day in most patients.L19809 The systemic availability of sirolimus is approximately 14%. In healthy subjects, the mean bioavailability of sirolimus after administration of the tablet is approximately 27% higher relative to the solution. Sirolimus tablets are not bioequivalent to the solution; however, clinical equivalence has been demonstrated at the 2 mg dose level. Sirolimus concentrations, following the administration of Rapamune Oral Solution to stable renal transplant patients, are dose-proportional between 3 and 12 mg/m2.L19809

Metabolisme

Sirolimus undergoes extensive metabolism in the intestinal wall and liver. Sirolimus is primarily metabolized by O-demethylation and/or hydroxylation via CYP3A4 to form seven major metabolites, including hydroxy, demethyl, and hydroxydemethyl metabolites, which are pharmacologically inactive. Sirolimus also undergoes counter-transport from enterocytes of the small intestine into the gut lumen.L19809

Rute Eliminasi

Following oral administration of 14C sirolimus in healthy subjects, about 91% of the radioactivity was recovered from feces and only 2.2% of the radioactivity was detected in urine. Some of the metabolites of sirolimus are also detectable in feces and urine.L19809

Interaksi Makanan

3 Data
  • 1. Avoid grapefruit products. Grapefruit inhibits the CYP3A4 metabolism of sirolimus and increases its serum concentration.
  • 2. Exercise caution with St. John's Wort. This herb induces CYP3A4 and P-gp; thus it may reduce sirolimus serum concentrations.
  • 3. Take with or without food. Take consistently with regard to food.

Interaksi Obat

1327 Data
Denosumab The risk or severity of adverse effects can be increased when Denosumab is combined with Sirolimus.
Peginterferon alfa-2a The risk or severity of adverse effects can be increased when Peginterferon alfa-2a is combined with Sirolimus.
Interferon alfa-n1 The risk or severity of adverse effects can be increased when Interferon alfa-n1 is combined with Sirolimus.
Interferon alfa-n3 The risk or severity of adverse effects can be increased when Interferon alfa-n3 is combined with Sirolimus.
Peginterferon alfa-2b The risk or severity of adverse effects can be increased when Peginterferon alfa-2b is combined with Sirolimus.
Interferon gamma-1b The risk or severity of adverse effects can be increased when Interferon gamma-1b is combined with Sirolimus.
Interferon alfa-2a The risk or severity of adverse effects can be increased when Interferon alfa-2a is combined with Sirolimus.
Gemtuzumab ozogamicin The risk or severity of adverse effects can be increased when Gemtuzumab ozogamicin is combined with Sirolimus.
Pegaspargase The risk or severity of adverse effects can be increased when Pegaspargase is combined with Sirolimus.
Interferon beta-1b The risk or severity of adverse effects can be increased when Interferon beta-1b is combined with Sirolimus.
Interferon alfacon-1 The risk or severity of adverse effects can be increased when Interferon alfacon-1 is combined with Sirolimus.
Rituximab The risk or severity of adverse effects can be increased when Rituximab is combined with Sirolimus.
Basiliximab The risk or severity of adverse effects can be increased when Basiliximab is combined with Sirolimus.
Muromonab The risk or severity of adverse effects can be increased when Muromonab is combined with Sirolimus.
Ibritumomab tiuxetan The risk or severity of adverse effects can be increased when Ibritumomab tiuxetan is combined with Sirolimus.
Tositumomab The risk or severity of adverse effects can be increased when Tositumomab is combined with Sirolimus.
Alemtuzumab The risk or severity of adverse effects can be increased when Alemtuzumab is combined with Sirolimus.
Alefacept The risk or severity of adverse effects can be increased when Alefacept is combined with Sirolimus.
Efalizumab The risk or severity of adverse effects can be increased when Efalizumab is combined with Sirolimus.
Antithymocyte immunoglobulin (rabbit) The risk or severity of adverse effects can be increased when Antithymocyte immunoglobulin (rabbit) is combined with Sirolimus.
Interferon alfa-2b The risk or severity of adverse effects can be increased when Interferon alfa-2b is combined with Sirolimus.
Daclizumab The risk or severity of adverse effects can be increased when Daclizumab is combined with Sirolimus.
Phenylalanine The risk or severity of adverse effects can be increased when Phenylalanine is combined with Sirolimus.
Cladribine Sirolimus may increase the immunosuppressive activities of Cladribine.
Carmustine The risk or severity of adverse effects can be increased when Carmustine is combined with Sirolimus.
Bleomycin The risk or severity of adverse effects can be increased when Bleomycin is combined with Sirolimus.
Chlorambucil The risk or severity of adverse effects can be increased when Chlorambucil is combined with Sirolimus.
Raltitrexed The risk or severity of adverse effects can be increased when Raltitrexed is combined with Sirolimus.
Mitomycin The risk or severity of adverse effects can be increased when Mitomycin is combined with Sirolimus.
Floxuridine The risk or severity of adverse effects can be increased when Floxuridine is combined with Sirolimus.
Tioguanine The risk or severity of adverse effects can be increased when Tioguanine is combined with Sirolimus.
Dexrazoxane The risk or severity of adverse effects can be increased when Dexrazoxane is combined with Sirolimus.
Trifluridine The risk or severity of adverse effects can be increased when Trifluridine is combined with Sirolimus.
Gemcitabine The risk or severity of adverse effects can be increased when Gemcitabine is combined with Sirolimus.
Epirubicin The risk or severity of adverse effects can be increased when Epirubicin is combined with Sirolimus.
Lenalidomide The risk or severity of adverse effects can be increased when Lenalidomide is combined with Sirolimus.
Altretamine The risk or severity of adverse effects can be increased when Altretamine is combined with Sirolimus.
Cisplatin The risk or severity of adverse effects can be increased when Cisplatin is combined with Sirolimus.
Oxaliplatin The risk or severity of adverse effects can be increased when Oxaliplatin is combined with Sirolimus.
Fluorouracil The risk or severity of adverse effects can be increased when Fluorouracil is combined with Sirolimus.
Propylthiouracil The risk or severity of adverse effects can be increased when Propylthiouracil is combined with Sirolimus.
Pentostatin The risk or severity of adverse effects can be increased when Pentostatin is combined with Sirolimus.
Linezolid The risk or severity of adverse effects can be increased when Linezolid is combined with Sirolimus.
Clofarabine The risk or severity of adverse effects can be increased when Clofarabine is combined with Sirolimus.
Pemetrexed The risk or severity of adverse effects can be increased when Pemetrexed is combined with Sirolimus.
Sulfasalazine The risk or severity of adverse effects can be increased when Sulfasalazine is combined with Sirolimus.
Dacarbazine The risk or severity of adverse effects can be increased when Dacarbazine is combined with Sirolimus.
Penicillamine The risk or severity of adverse effects can be increased when Penicillamine is combined with Sirolimus.
Mechlorethamine The risk or severity of adverse effects can be increased when Sirolimus is combined with Mechlorethamine.
Azacitidine The risk or severity of adverse effects can be increased when Sirolimus is combined with Azacitidine.
Carboplatin The risk or severity of adverse effects can be increased when Sirolimus is combined with Carboplatin.
Azathioprine The risk or severity of adverse effects can be increased when Sirolimus is combined with Azathioprine.
Hydroxyurea The risk or severity of adverse effects can be increased when Sirolimus is combined with Hydroxyurea.
Mycophenolic acid The risk or severity of adverse effects can be increased when Sirolimus is combined with Mycophenolic acid.
Mercaptopurine The risk or severity of adverse effects can be increased when Sirolimus is combined with Mercaptopurine.
Thalidomide The metabolism of Sirolimus can be increased when combined with Thalidomide.
Melphalan The risk or severity of adverse effects can be increased when Sirolimus is combined with Melphalan.
Fludarabine The risk or severity of adverse effects can be increased when Sirolimus is combined with Fludarabine.
Flucytosine The risk or severity of adverse effects can be increased when Sirolimus is combined with Flucytosine.
Capecitabine The risk or severity of adverse effects can be increased when Sirolimus is combined with Capecitabine.
Procarbazine The risk or severity of adverse effects can be increased when Sirolimus is combined with Procarbazine.
Idarubicin The risk or severity of adverse effects can be increased when Sirolimus is combined with Idarubicin.
Eculizumab The risk or severity of adverse effects can be increased when Sirolimus is combined with Eculizumab.
Decitabine The risk or severity of adverse effects can be increased when Sirolimus is combined with Decitabine.
Nelarabine The risk or severity of adverse effects can be increased when Sirolimus is combined with Nelarabine.
Stepronin The risk or severity of adverse effects can be increased when Sirolimus is combined with Stepronin.
Castanospermine The risk or severity of adverse effects can be increased when Sirolimus is combined with Castanospermine.
Vorinostat The risk or severity of adverse effects can be increased when Sirolimus is combined with Vorinostat.
2-Methoxyethanol The risk or severity of adverse effects can be increased when Sirolimus is combined with 2-Methoxyethanol.
Brequinar The risk or severity of adverse effects can be increased when Sirolimus is combined with Brequinar.
Pirfenidone The risk or severity of adverse effects can be increased when Sirolimus is combined with Pirfenidone.
Belinostat The risk or severity of adverse effects can be increased when Sirolimus is combined with Belinostat.
Interferon alfa The risk or severity of adverse effects can be increased when Sirolimus is combined with Interferon alfa.
Glatiramer The risk or severity of adverse effects can be increased when Sirolimus is combined with Glatiramer.
Briakinumab The risk or severity of adverse effects can be increased when Sirolimus is combined with Briakinumab.
Human interferon omega-1 The risk or severity of adverse effects can be increased when Sirolimus is combined with Human interferon omega-1.
Mepolizumab The risk or severity of adverse effects can be increased when Sirolimus is combined with Mepolizumab.
Abetimus The risk or severity of adverse effects can be increased when Sirolimus is combined with Abetimus.
Belatacept The risk or severity of adverse effects can be increased when Sirolimus is combined with Belatacept.
Bendamustine The risk or severity of adverse effects can be increased when Sirolimus is combined with Bendamustine.
Pralatrexate The risk or severity of adverse effects can be increased when Sirolimus is combined with Pralatrexate.
Wortmannin The risk or severity of adverse effects can be increased when Sirolimus is combined with Wortmannin.
Eribulin The risk or severity of adverse effects can be increased when Sirolimus is combined with Eribulin.
Belimumab The risk or severity of adverse effects can be increased when Sirolimus is combined with Belimumab.
Teriflunomide The risk or severity of adverse effects can be increased when Sirolimus is combined with Teriflunomide.
Dimethyl fumarate The risk or severity of adverse effects can be increased when Sirolimus is combined with Dimethyl fumarate.
Obinutuzumab The risk or severity of adverse effects can be increased when Sirolimus is combined with Obinutuzumab.
Vedolizumab The risk or severity of adverse effects can be increased when Sirolimus is combined with Vedolizumab.
Blinatumomab The risk or severity of adverse effects can be increased when Sirolimus is combined with Blinatumomab.
Dinutuximab The risk or severity of adverse effects can be increased when Sirolimus is combined with Dinutuximab.
Tixocortol The risk or severity of adverse effects can be increased when Sirolimus is combined with Tixocortol.
Peginterferon beta-1a The risk or severity of adverse effects can be increased when Sirolimus is combined with Peginterferon beta-1a.
Antilymphocyte immunoglobulin (horse) The risk or severity of adverse effects can be increased when Sirolimus is combined with Antilymphocyte immunoglobulin (horse).
Tepoxalin The risk or severity of adverse effects can be increased when Sirolimus is combined with Tepoxalin.
Ixekizumab The risk or severity of adverse effects can be increased when Sirolimus is combined with Ixekizumab.
Ravulizumab The risk or severity of adverse effects can be increased when Sirolimus is combined with Ravulizumab.
Pirarubicin The risk or severity of adverse effects can be increased when Sirolimus is combined with Pirarubicin.
Peficitinib The risk or severity of adverse effects can be increased when Sirolimus is combined with Peficitinib.
Brodalumab The risk or severity of adverse effects can be increased when Sirolimus is combined with Brodalumab.
Sirukumab The risk or severity of adverse effects can be increased when Sirolimus is combined with Sirukumab.

Target Protein

Serine/threonine-protein kinase mTOR MTOR

Referensi & Sumber

Synthesis reference: Madhup K. Dhaon, Chi-nung Hsiao, Subhash R. Patel, Peter J. Bonk, Sanjay R. Chemburkar, Yong Y. Chen, "One pot synthesis of tetrazole derivatives of sirolimus." U.S. Patent US20080167335, issued July 10, 2008.
Artikel (PubMed)
  • PMID: 16103051
    Sun SY, Rosenberg LM, Wang X, Zhou Z, Yue P, Fu H, Khuri FR: Activation of Akt and eIF4E survival pathways by rapamycin-mediated mammalian target of rapamycin inhibition. Cancer Res. 2005 Aug 15;65(16):7052-8.
  • PMID: 15365568
    Chan S: Targeting the mammalian target of rapamycin (mTOR): a new approach to treating cancer. Br J Cancer. 2004 Oct 18;91(8):1420-4.
  • PMID: 12742462
    Sehgal SN: Sirolimus: its discovery, biological properties, and mechanism of action. Transplant Proc. 2003 May;35(3 Suppl):7S-14S.
  • PMID: 25188522
    Peters T, Traboulsi D, Tibbles LA, Mydlarski PR: Sirolimus: a therapeutic advance for dermatologic disease. Skin Therapy Lett. 2014 Jul-Aug;19(4):1-4.
  • PMID: 15859902
    Yakupoglu YK, Kahan BD: Sirolimus: a current perspective. Exp Clin Transplant. 2003 Jun;1(1):8-18.
  • PMID: 24508508
    Li J, Kim SG, Blenis J: Rapamycin: one drug, many effects. Cell Metab. 2014 Mar 4;19(3):373-9. doi: 10.1016/j.cmet.2014.01.001. Epub 2014 Feb 6.
  • PMID: 11863212
    Hancock E, Tomkins S, Sampson J, Osborne J: Lymphangioleiomyomatosis and tuberous sclerosis. Respir Med. 2002 Jan;96(1):7-13. doi: 10.1053/rmed.2001.1206.

Contoh Produk & Brand

Produk: 62 • International brands: 0
Produk
  • Fyarro
    Injection, powder, lyophilized, for suspension • 5 mg/1mL • Intravenous • US • Approved
  • Gd-sirolimus
    Solution • 1.0 mg / mL • Oral • Canada • Generic • Approved
  • Gd-sirolimus
    Tablet • 1.0 mg • Oral • Canada • Generic • Approved
  • Gd-sirolimus
    Tablet • 2 mg • Oral • Canada • Generic • Approved
  • Gd-sirolimus
    Tablet • 5 mg • Oral • Canada • Generic • Approved
  • Hyftor
    Gel • 2.0 mg/1g • Topical • US • Approved
  • Hyftor
    Gel • 2 mg/g • Topical • EU • Approved
  • Rapamune
    Tablet, sugar coated • 1 mg/1 • Oral • US • Approved
Menampilkan 8 dari 62 produk.

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